This invention relates to a method and a system for producing nitric oxide mixed with air or other gases for use in medicine.
Nitric oxide (NO) is crucial to many biological systems (G. Kolada, The New York Times, Jul. 2, 1991, p. C1.). Kolada indicates that nitric oxide mediates the control of blood pressure, helps the immune system kill invading parasites that enter cells, stops cancer cells from dividing, transmits signals between brain cells, and contributes to the large scale death of brain cells that can debilitate people with strokes or Huntington's disease.
It was shown that nitric oxide mediates relaxation of gastric smooth muscle (K. M. Desai et al., Nature, Vol. 351, Jun. 6, 1991, p. 477). Desai et al. demonstrated that adaptive relaxation in isolated stomach of the guinea pig is mediated by a non-adrenergic, non-cholinergic (NANC) neurotransmitter. Furthermore, they showed that this NANC neurotransmitter is undistinguishable from nitric oxide derived from L-arginine. The authors concluded that it is likely that nitric oxide is a final common mediator of smooth muscle relaxation.
Smooth muscle is present, for example, in the walls of the blood vessels, bronchi, gastrointestinal tract, and urogenital tract. Administration of nitric oxide gas to the lung by inhalation could produce localized smooth muscle relaxation without systemic side effects. This characteristic can be used in medicine to treat bronchial constriction and pulmonary hypertension, pneumonia, etc.
Nitric oxide is now known to be an important naturally occurring local cellular hormone, the so-called endothelium derived relaxing factor. This factor is produced in many cells (i.e., endothelial cells lining blood vessels, bronchi, intestines, bladder, uterus, and other hollow organs) by the enzyme nitric oxide synthetase (now known to be a family of at least six enzymes) from arginine. Once NO is released, it binds rapidly to the enzyme guanylate cyclase in smooth muscle cells, increasing cyclic guanylate monophosphate (cyclic GMP), reducing intracellular calcium levels and thereby causing smooth muscle relaxation.
Inhaled nitric oxide, as demonstrated by a number of pilot studies in animals and humans, is a potent local pulmonary vasodilator and bronchodilator with no systemic effects. NO has the remarkable ability to improve the matching of ventilation with perfusion, thereby increasing the injured lungs oxygen transport efficiency and raising the arterial oxygen tension. To date, NO is the only pulmonary vasoactive agent known with such selective properties and thus has enormous potential in the treatment of acute and chronic lung diseases with pulmonary bronchoconstriction and vasoconstriction.
Bronchodilators are drugs which are used to reduce airway reactivity and to reverse bronchospasm caused by a variety of diseases, such as asthma, exacerbations of chronic pulmonary obstructive disease, allergic and anaphylactic reactions and others. Several classes of bronchodilators have been employed, each with its own mode of action, tolerance and undesirable side effects.
Beta agonists, represented by epinephrine and isoproterenol, induce bronchodilation by stimulating receptors that increase adenyl cyclase concentrations and the production of intracellular cyclic adenosine monophosphate (AMP). They can be delivered by aerosol, orally or parenterally. Administration of these agents causes significant adverse cardiac effects such as tachycardias, heart palpitations, changes in blood pressure and also other side effects including anxiety, tremors, nausea and headaches. Newer, beta.sub.2 -selective agonists, for example, albuterol have fewer side effects and somewhat slower onset of action.
Theophylline preparations are less potent bronchodilators than beta agonists and have a narrower therapeutic toxic window. The mechanism responsible for the bronchodilator effect of theophylline is probably via cyclic AMP. Side effects commonly caused by theophylline are nervousness, nausea, vomiting, anorexia and headache. Furthermore, if taken at very high levels, theophylline can cause cardiac arrhythmias and seizures.
Anticholinergic drug such as atropine methylnitrate and ipratrobium bromide administered by aerosol are effective bronchodilators with relatively few side effects. However, they have a slow onset of action, and 60 to 90 minutes may be required before peak bronchodilation is achieved.
Nitric oxide is unique in that it combines a rapid onset of action occurring within seconds with the absence of systemic effects. Once inhaled, it diffuses through the pulmonary vasculature into the bloodstream, where it is rapidly inactivated by combination with hemoglobin. Therefore, the bronchodilator effects of inhaled nitric oxide are limited to the airway and the vasodilatory effects of inhaled nitric oxide are limited to the pulmonary vasculature.
This unique ability of nitric oxide to dilate pulmonary vessels selectively can be used also in the treatment of either acute or chronic pulmonary hypertension. Pulmonary hypertension is defined as an elevation of the mean pulmonary arterial pressure over the normal levels of 12 to 15 millimeters Hg.
Acute pulmonary hypertension is produced by vasoconstriction of pulmonary vessels in response to sudden hypoxia due to, for example, pneumonia, pulmonary embolus, or acidosis. Acute pulmonary hypertension is a potentially reversible phenomenon and successful treatment of the precipitating condition leads to normalization of the pulmonary pressures. Persistent hypoxia, however, induces permanent structural changes in the pulmonary vasculature, and chronic pulmonary hypertension ensues. The main causes of chronic pulmonary hypertension are chronic obstructive pulmonary disease, recurring multiple small emboli, heart disease such as mitral stenosis or atrial septal defect, and idiopathic primary pulmonary hypertension. Pulmonary hypertension has also been implicated in several other life-threatening conditions such as adult respiratory distress syndrome and persistent pulmonary hypertension of the newborn.
To date, treatment of pulmonary hypertension has been attempted with several vasodilator drugs including nitroprusside, hydralazine, nifedipine, captopril and others. Major limitation of these agents has been their non-selective reduction of both pulmonary and systemic blood pressures. In contrast, inhaled nitric oxide produces vasodilation limited to pulmonary vessels and thus offers a revolutionary therapeutic advantage.
An inhaler designed to deliver nitric oxide is described in U.S. patent application Ser. No. 07/767,234, filed Sep. 23, 1991, assigned to the same assignee as this application, and incorporated herein by reference.